POS1365 STRUCTURAL SEVERITY IN KNEE OSTEOARTHRITIS IMPACTS TREATMENT RESPONSE: A POST HOC POOLED ANALYSIS OF LORECIVIVINT CLINICAL TRIALS
Authors: Y. Yazici, C. Swearingen, H. Ghandehari, I. Simsek, S. Kennedy, J. Tambiah, T. Mcalindon
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is a leading cause of disability globally, with disease burden expected to rise <sup>[1]</sup>. Unmet needs remain for safe and efficacious treatments for symptoms and structural modification. Difficulties assessing pain and joint structure in clinical trials exist due to disease heterogeneity. This post hoc analysis of lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor thought to modulate Wnt and inflammatory pathways, examined the structural heterogeneity of participants enrolled in Phase 2 and 3 LOR trials and associated treatment responses within KL grade subgroups. <h3>Objectives</h3> To identify potential relationships between OA pain and knee joint structural damage which may aid future clinical trial design. <h3>Methods</h3> Data was analyzed from two Phase 2 (OA-02, NCT02536833; OA-04, NCT03122860), and two Phase 3 trials (OA-10, NCT04385303; OA-11, NCT03928184) trials. In all trials, participants had ACR-defined (clinical and radiographic) knee OA, Kellgren-Lawrence (KL) grades 2-3. For OA-04, OA-10 and OA-11, additional pain inclusion criteria included Pain Numeric Rating Scale (NRS) [0-10] ≥4 and ≤8 in the target knee and &lt;4 in the contralateral knee. Baseline JSW for each study was compared using cumulative frequency distribution plots by KL grade; percentages of subjects with JSW &lt; 3mm for each study was also summarized to provide a surrogate for loss of ~50% healthy JSW (Deep et al. <i>JBJS</i> 2003). For the trials which captured Pain NRS outcomes, treatment responses were assessed according to KL grade. For all treatment-related outcomes, change from baseline was estimated using baseline-adjusted ANCOVA at each timepoint. <h3>Results</h3> KL 2 participants with baseline mJSW &lt; 3 mm comprised 16% (OA-02), 21% (OA-04), 30% (OA-10) and 49% (OA-11). KL 3 participants with baseline mJSW &lt; 3 mm comprised 55% (OA-02), 53% (OA-04), 81% (OA-10) and 88% (OA-11) (Figure 1) Beneficial treatment effect of LOR vs. PBO was seen for KL 2 subgroup in OA-04 and OA-10, but not in OA-11. Beneficial treatment effect of LOR was seen only in OA-04 for KL 3 at week 12. <h3>Conclusion</h3> In this post hoc analysis, substantial heterogeneity in baseline mJSWs existed across LOR clinical trials within the KL grade 2-3 inclusion criteria. Participants with less structurally advanced knee OA showed greater pain treatment responses to 0.07 mg LOR compared to those with more advanced disease. These data support the hypothesis that the amount of OA structural damage is associated with the pain of knee OA and that earlier LOR intervention may improve outcomes. <h3>Reference</h3> [1]Wallace, IJ et al. <i>PNAS</i> 2017 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Yusuf Yazici Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Christopher Swearingen Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Heli Ghandehari Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Ismail Simsek Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Sarah Kennedy Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Jeymi Tambiah Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Timothy McAlindon Consultant of: Biosplice Therapeutics, Grant/research support from: Biosplice Therapeutics.